tbuckley/cabot-search huggingface dataset:
Phase 2 clinical study evaluating the efficacy and safety of disitamab vedotin with or without pembrolizumab in patients with HER2-expressing urothelial carcinoma (RC48G001).
Authors: Thomas Powles, Evan Y. Yu, Gopa Iyer, Matthew T Campbell, Yohann Loriot, Maria De Santis, Peter H. O'Donnell, Earle F Burgess, Andrea Necchi, Laurence E. M. Krieger, Nobuaki Matsubara, Vadim S Koshkin, Wei Zhang, Mari Ichimaru, Matt D. Galsky
Journal: Journal of Clinical Oncology (2023)

TPS594 Background: Urothelial carcinoma (UC) is the 10th most diagnosed cancer worldwide, and nearly 50% of patients cannot tolerate the current first-line (1L) standard of care. There is a need to improve outcomes in 1L and later lines of therapy. HER2 is overexpressed in UC and may be associated with poor outcomes. Despite this, no HER2-directed therapies are currently approved for UC. Disitamab vedotin (DV; RC48-ADC) is an investigational antibody-drug conjugate comprising a novel HER2-directed monoclonal antibody, disitamab, conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. DV elicits antitumor activity through multimodal mechanisms of action including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death. Methods: RC48G001 (NCT04879329) is a phase 2, multi-cohort, open-label, multicenter trial to evaluate DV in patients with HER2-expressing locally advanced/metastatic UC (LA/mUC). Patients are enrolled in 3 cohorts based on prior treatment and tumor HER2 expression by immunohistochemistry (IHC) and gene amplification (via in situ hybridization [ISH]), assessed centrally. Cohorts A and B are enrolling patients who have received prior systemic therapy (1 or 2 lines, including platinum-containing chemotherapy) and whose tumors are HER2-positive (IHC 3+, or 2+ and ISH-positive) or HER2-low (IHC 2+ and ISH-negative, or IHC 1+), respectively. Cohort C is enrolling 1L treatment-naive patients in the LA/mUC setting, whose tumors have HER2-positive or HER2-low expression. Cohorts A and B will evaluate DV as monotherapy (intravenous [IV] administration, once every 2 weeks [Q2W]). Cohort C will evaluate DV (IV, Q2W) +/– pembrolizumab (IV, Day 1 of each 6-week cycle). Patients in all cohorts must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group Performance Status of 0–1 in Cohorts A and B, and 0–2 in Cohort C. The primary endpoint is confirmed objective response rate (cORR) per blinded independent central review (BICR). Secondary endpoints include cORR by investigator assessment, overall survival, duration of response, progression-free survival, disease control rate per RECIST v1.1 by BICR and investigator, safety, and pharmacokinetic parameters. Enrollment for all cohorts is ongoing in North America and Europe, and planned in Latin America, Asia-Pacific, and Israel. Clinical trial information: NCT04879329 .
Impact of psychological distress on emergency room utilization and mortality among prostate cancer survivors.
Authors: Changchuan Jiang, Kaitlin Chidester, Alexandra Sanders, Stuthi Perimbeti, Lei Deng, Karan Jatwani, Arya Mariam Roy, Gurkamal S. Chatta, Dharmesh Gopalakrishnan
Journal: Journal of Clinical Oncology (2023)

343 Background: The population of prostate cancer (PCa) survivors has grown over the recent decades, with many reporting long-term treatment-related physical, emotional, and financial adverse effects resulting in greater psychological distress compared to males without a history of PCa. This study analyzes the prevalence of psychological distress among PCa survivors and its impact on emergency room (ER) utilization and overall survival. Methods: We identified a cohort of 3,453 PCa survivors from the 2000-2018 National Health Interview Survey (NHIS) linked to the National Death Index Mortality Files through Dec 31, 2019. Deaths that occurred during the first two years of follow-up were excluded from analyses to minimize the likelihood of reverse causation. The Kessler Psychological Distress Scale (K6) was used to quantify psychological distress. Severe, moderate, and none/low mental distress have been validated for thresholds K6≥13, 13&gt; K6 ≥5, and 5&gt; K6 ≥0. Its association with self-reported ER utilization during the 12 months preceding the survey and all-cause mortality was estimated using weighted multivariable logistic regression and Cox proportional hazards regression, respectively. Models were adjusted for age, sex, race, educational attainment, comorbidities, region, year of survey, smoking status, health insurance, functional limitations, and time since cancer diagnosis. Results: Among the 3,453 PCa survivors (mean [SD] age 68.5 [7.2] years; 2479 (77.9%] non-Hispanic White, 655 (14.1%) non-Hispanic Black; median time since cancer diagnosis:5 years), 435 (11.3%) and 96 (2.4%) reported moderate and severe psychological distress respectively. PCa survivors with psychological distress tend to be younger, less educated, single, and with multiple comorbid conditions, and functional limitations. 812(22.8%) of PCa survivors visited the ER during 12 months preceding the survey. During a median follow-up of 81 months, 937(25.5%) of survivors died of all causes. After adjusting for covariates, PCa survivors with severe psychological distress were at a higher risk of ER utilization and all-cause mortality than those with moderate or no distress. Conclusions: Psychological distress was associated with increased risk of ER utilization and all-cause mortality among PCa survivors. Greater efforts are needed to understand, recognize, and alleviate such distress, as well as to enhance social and mental/physical health support in this rapidly growing community of vulnerable cancer survivors. [Table: see text]
Performance characteristics of a tumor-informed circulating tumor DNA (ctDNA) minimal residual disease (MRD) assay in invasive bladder cancer in clinical practice.
Authors: Shoshana Mehler, Seth Guilbeau, Shmuel Somer, Kevin Reed, Heather Greene, Daniel A. Vaena, Axel Grothey, Brad Somer
Journal: Journal of Clinical Oncology (2023)

542 Background: Detection of minimal residual disease (MRD) is emerging as a potential risk stratification and surveillance tool in patients with resected bladder cancer to potentially direct adjuvant therapy and early intervention. Recently, the sensitivity of MRD testing for early detection of recurrence has been questioned. We sought to evaluate the real world diagnostic performance characteristics of the Signatera ctDNA assay in patients with stage 1-4 bladder cancer who either had transurethral resection of bladder tumor (TURBT) in addition to either chemoradiation or radical cystectomy. Methods: Patients with bladder cancer who underwent ctDNA MRD testing after resection for stage 1-4 disease from 03/2021 to 09/2022 were evaluated retrospectively. Both patients with single and serial ctDNA assays were included. Individual chart review was performed to collect demographic and clinical variables such as diagnosis, stage, pathology, imaging results, and treatment course. Results: MRD results from 19 patients were available, 9 of which had serial assays. 13/19 patients were found to have ctDNA positive results at any time point. The positivity rate at initial testing was associated with stage: Stage 1: 3/5 patients, of which 2 had TURBT and 1 Radical cystectomy, stage 2: 2/5, stage 3: 6/8, and stage 4: 0/1. Notably, of the 9 patients with serial assays, one patient’s result converted from negative to highly positive during surveillance, with subsequent decrease to low positive after adjuvant therapy. One patient had a result of 2 consecutive low positives initially, which was converted to negative after systemic therapy and radiation. 7/19 patients completed testing 3 or more times over a span of approximately 4-13 months, 2 of whom had negative results throughout. Most patients who were found to have positive ctDNA did demonstrate radiographic recurrence within 2-3 months of ctDNA detection. Conclusions: Positive ctDNA MRD after resection is common in bladder cancer. Tumor-informed ctDNA MRD testing has very high sensitivity, but a one-time negative test result does not exclude the presence of metastatic disease. The above data shows an association between cancer stage and positivity results, particularly for advanced stages. Stage I cases with positive results can likely be explained by inadequate resection. Increases in ctDNA may represent early recurrence and can potentially be salvaged with early systemic therapy reverting to negative ctDNA. Prospective randomized and non-randomized studies are evaluating the clinical utility of ctDNA MRD testing in bladder cancer, and analysis of Signatera ctDNA assays will largely contribute to these efforts.
Outcomes of patients with brain metastases from renal cell carcinoma treated with first-line therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Kosuke Takemura, Audreylie Lemelin, Matthew Scott Ernst, Connor Wells, Naveen S. Basappa, Bernadett Szabados, Thomas Powles, Ian D. Davis, Lori Wood, Anil Kapoor, Rana R. McKay, Jae-Lyun Lee, Luis A Meza, Sumanta Monty Pal, Frede Donskov, Takeshi Yuasa, Benoit Beuselinck, Georges Gebrael, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2023)

600 Background: The outcomes of patients with brain metastases from renal cell carcinoma (RCC) are not well characterized due to exclusion of these patients from clinical trials. Methods: Using the IMDC, patients with brain metastases from RCC at the initiation of first-line therapy were analyzed. Baseline patient characteristics, brain-directed local therapies, clinician assessment of best overall response as per RECIST 1.1, and overall survival (OS) were compared across first-line therapies, namely immuno-oncology (IO)-based combination therapy (IO/IO or IO/vascular endothelial growth factor (VEGF)) and anti-VEGF monotherapy (sunitinib or pazopanib). Results: The overall cohort of patients with brain metastases included 775 patients, consisting of 78/1298 (6.0%) and 697/8633 (8.1%) in the IO-based and anti-VEGF cohorts, respectively (p = 0.009). Among the baseline patient characteristics, only the proportion of patients receiving whole-brain radiotherapy differed significantly across the IO-based and anti-VEGF cohorts with proportions of 25.0% and 55.7%, respectively (p &lt; 0.001). Best overall response in all disease sites was 3.4% complete response (CR), 25.9% partial response (PR), 39.7% stable disease (SD), and 31% progressive disease (PD) in the IO-based cohort, whereas it was 0.7% CR, 29.6% PR, 36.7% SD, and 33.0% PD in the anti-VEGF cohort (p = 0.223). The following factors were significantly associated with longer OS on multivariable analysis: IMDC favourable-/intermediate-risk (HR 0.49, 95% CI 0.37–0.65; p &lt; 0.001), IO-based combination therapy (HR 0.51, 95% CI 0.29–0.92; p = 0.026), neurosurgery (HR 0.62, 95% CI 0.47–0.83; p = 0.001), and stereotactic radiosurgery (HR 0.64, 95% CI 0.49–0.84; p = 0.001). Conclusions: Patients with brain metastases receiving IO-based combination therapy may have longer OS than those receiving anti-VEGF monotherapy. Brain-directed local therapies including neurosurgery and stereotactic radiosurgery were associated with longer OS. [Table: see text]
Local and systemic therapies for renal cell carcinoma with brain metastases: A single-institution series.
Authors: Teja Ganta, Eric James Miller, Jonathan Forrest Anker, Matt D. Galsky, Kai Tsao
Journal: Journal of Clinical Oncology (2023)

627 Background: Current practice guidelines for the management of renal cell carcinoma (RCC) with brain metastases (BM) recommend a multimodal approach with systemic therapy, radiation, and/or surgery. The purpose of this study is to assess treatment patterns and identify prognostic factors for survival in this population. Methods: This retrospective, single-center study evaluated patients with RCC who were diagnosed with metastatic disease between 2015-2020 and were identified to have BM at any point in their care. Fisher's exact test and Mann-Whitney test were used to compare differences among groups. Kaplan-Meier curves were used to estimate time to events from the date of BM diagnosis. Univariate Cox proportional hazards model was used to estimate the effect of factors on survival. Results: 29 patients are included. Median follow-up was 25 months (range: 0.5-73). 16 (55%) patients presented with BM at the time of diagnosis of metastatic disease. 17 (58%) were treated with radiation. 8 (28%) were treated with surgery of which 7 also received radiation. Median overall survival was 10 months (95% CI: 7-not reached). Patients received a median of one (range 0-4) system therapy regimen after diagnosis of BM. 19 (66%) patients were exposed to at least one class of medication therapy for management of BM while 10 (34%) were exposed to two or more classes. 10 patients experienced long term survival (defined as survival ≥12 months). Patients with long term survival were more likely to have received radiation (90% vs 42%; P=0.02). However, use of radiation was not associated with survival (HR 0.47, 95% CI 0.1-1.3). Conclusions: The study is limited by sample size but suggests there is a population of patients with RCC with BM who can experience long term survival. Optimal selection for patients with BM that can be feasibly treated within radiation fields appears favorable. Most patients are not exposed to more than one systemic medication class during their care. Additional research is needed to compare efficacy in BM to guide first line systemic therapy selection. [Table: see text]
Factors associated with poor survival outcomes in patients with prostate cancer (PCa) with radiographic disease progression in the setting of low PSA.
Authors: Mohamed E. Ahmed, Ahmed Mahmoud, Jack R. Andrews, Matthew Lee, Daniel S Childs, Ayse T. Kendi, Geoffrey Johnson, Matthew K. Tollefson, Stephen A. Boorjian, R. Jeffrey Karnes, Eugene D. Kwon
Journal: Journal of Clinical Oncology (2023)

60 Background: Recent studies, including a post-hoc analysis of the ARCHES trial, highlight radiographic disease progression (rDP) occurring without concordant rise in prostate specific antigen (PSA). In a previous study by our group, we reported that almost 40% of patients on 2 nd generation hormone therapy experience rDP with non-rising PSA and have poor survival outcomes. The current analysis more specifically focuses on the subgroup of patients with rDP occurring at low PSA (&lt;0.5 ng/dL) and describes factors associated with poorer survival outcomes in this patient population. Methods: In a single institution study, we reviewed the prospectively maintained Mayo Clinic C-11 Choline PET registry for patients treated between 2011 and 2021, who experienced rDP at low PSA (value &lt; 0.5 ng/mL). Disease progression on C-11 choline PET was confirmed by either tissue biopsy or subsequent response to therapy. We investigated factors associated with poor cancer-specific survival outcomes in univariable and multivariable cox regression analyses. Results: In total, 220 (16%) patients experiencing rDP at low PSA were identified. Median (IQR) age at rDP was 67.91 (61.10 – 73.87) yrs., median (IQR) primary Gleason score was 9 (7-9), and median (IQR) PSA was 0.17 (0 – 0.32) ng/ml. 75% of the patients (n=166) had CRPC disease status at time of rDP. Prior systemic treatments included 2 nd generation HT in 18% (n= 40) and chemotherapy in 31% (n=70). Sites of rDP were divided into 7% local (n=16), 42% lymph nodes (n=91), 43% bone (n=95), and 8% visceral metastases (n=18). Over a median follow-up duration of 55 months, 46% of patients (n=100) reported death. Factors associated with poor survival outcomes are demonstrated in the table and include age at rDP, CRPC status, and disease location (P-value &lt;0.05). Conclusions: We found that radiographic disease progression commonly occurs at low PSA (&lt;0.5 ng/mL). CRPC-disease status and the development of visceral metastases are associated with particularly poor survival outcomes. To identify early progression, monitoring with imaging may be warranted, even in the patients with low PSA. [Table: see text]
Cost-effectiveness analysis of seven treatment regimens in metastatic hormone-sensitive prostate cancer (mHSPC): A public payer perspective using network meta-analysis.
Authors: Manish Kohli, Maura Dougherty, Zachary Cutshall, Rylee Beckstead, Rhea Kohli, Benjamin Haaland, Richard Nelson, Minkyoung Yoo
Journal: Journal of Clinical Oncology (2023)

268 Background: Recently several new treatment regimens have been approved for treating mHSPC, building on the previous standard of care using androgen deprivation therapy (ADT) alone. These include docetaxel+ADT (DA), Abiraterone Acetate+Prednisone+ADT (AAP), Apalutamide+ADT (AAT), Enzalutamide+ADT (ET), Darolutamide+Docetaxel+ADT (DAD) and Abiraterone+Prednisone+ADT+Docetaxel (AAD). There are no current predictive biomarkers for choosing any specific regimen. The goal of this study was to determine the cost-effectiveness of these new treatments from the US public sector perspective with a lifetime horizon. Methods: We developed a partitioned survival model in which mHSPC patients transitioned between three health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a network meta-analysis. A Bayesian network meta-analysis of seven clinical trials included 7,208 patients. The effectiveness outcome in our model was quality-adjusted life-years (QALYs) with utility values obtained from published literature. Costs in our model included those associated with treatment regimens and subsequent therapies, terminal care, and for managing grade 3-4 drug related adverse events, and were obtained from the Federal Supply Schedule and published literature. Results: Average lifetime costs ranged from $154,139 (AAP) to $770,848 (DAD) and mean QALYs ranged from 3.33 (ADT) to 5.08 (ET). All treatment strategies other than AAP and ET were eliminated due to dominance. Compared to AAP, the incremental cost-effectiveness ratio for ET was $484,943/QALY. Results from our analysis including all regimens are shown. Conclusions: Our simulation model found that ET in mHSPC state yielded the most QALYs and would be the most cost-effective option with a WTP threshold as high as $500,000/QALY. However, for a WTP threshold of $150,000/QALY, AAP was the most cost-effective treatment strategy. [Table: see text]
Phase II multi-center study of sintilimab in combination with axitinib in patients with advanced fumarate hydratase-deficient renal cell carcinoma.
Authors: Xingming Zhang, Haoyang Liu, Yaowen Zhang, Junjie Zhao, Yuntian Chen, Guangxi Sun, Xinan Sheng, Yongquan Wang, Kan Gong, Xiaodong Liu, Rui Huang, Qiang Wei, Xiang Li, Jiyan Liu, Pengfei Shen, Ni Chen, Jin Yao, Zhenhua Liu, Hao Zeng
Journal: Journal of Clinical Oncology (2023)

685 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and highly aggressive cancer mainly caused by germline or somatic aberrant of FH gene. Unfortunately, there are no standard treatment. Here we report the preliminary results of a phase II study investigating the efficacy and safety of sintilimab in combination with axitinib in patients with FH-RCC. Methods: Patients were treated at mutli-center in hospitals of the republic of China. Eligibility criteria included age ≥ 18 years and newly diagnosed as FH-RCC by FH immunohistochemistry and next-generation sequencing or multiplex ligation-dependent probe amplification. Patients received sintilimab (intravenous injection, every 3 week) in combination with axitinib (5mg, orally taken per day) as first-line treatment until disease progression or intolerant to treatment. The primary end point was objective response rate (ORR; RECIST v1.1). This study is registered with ClinicalTrials.gov, NCT04387500. Results: Between July 2021 and October 2022, 21 patients were enrolled. At this preliminary analysis (data cutoff, October, 2022), median follow-up was 9 months (0.9-15.2 months). Nineteen patients were available for efficacy assessment. Confirmed complete response rate was 15.8% (3/19), ORR was 63.1% (12/19). Disease-controlled rate (DCR) was 89.4% (17/19). The median of progression-free survival (PFS) was not reached, with a high 12-month PFS rate of 72.3%. All grade and ≥ 3 treatment-emergent adverse events occurred in 95% (20/21) and 23.8% (5/21), respectively. Conclusions: Sintilimab in combination with Axitinib had a manageable safety profile and achieved a promising tumor response rate in patients with advanced FH-RCC. The trial is an ongoing study, with a total of planned 41 patients from 8 sites. The study start date was June 2, 2021. Clinical trial information: NCT04387500 .
Survival outcomes and toxicity in older adults with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor targeted (ART) therapies.
Authors: George Slade Mellgard, Zakaria Chakrani, Stephen Mccroskery, Nathaniel Saffran, Nicole Taylor, Bobby Chi-Hung Liaw, Matt D. Galsky, William K. Oh, Kai Tsao, Vaibhav G. Patel
Journal: Journal of Clinical Oncology (2023)

117 Background: Prostate cancer (PCa) and especially advanced PCa largely affects older adults with a median age of diagnosis of 67. Despite ART’s role as a mainstay of treatment (tx) in advanced PCa, little is known about its risks/benefits in older adults. We aimed to examine survival outcomes and safety in patients (pts) with mCRPC ≥75 years-old (y.o) on ART. Methods: The records of mCRPC pts treated with ART at the Mount Sinai Hospital between 2010 and 2021 were screened for demographics, medical history, ART course, tx toxicity, and survival outcomes. PSA progression free survival (PFS) between pts ≥75 y.o and pts ≤75 y.o was assessed as the primary outcome. Secondary outcomes were overall survival (os) and tx toxicity. Tx toxicity was evaluated using physician documented tx side-effects (SE)s. Fischer’s exact was used to compare baseline characteristics and tx SEs. Cox proportional hazards models were used to compare survival outcomes. Results: Of 153 pts, 97 were &lt; 75 y.o and 56 were ≥75 y.o. Within the &lt;75 y.o group, 17 (17.5%) were post-chemo compared to 7 (12.5%) in the ≥75 group (p = .493) Relevant baseline characteristics (ECOG ≥2, Race, Gleason 4-5, hospitalizations, and CCI) were not significantly different. Median PSA PFS was 14.2 (≥75 y.o) and 17.3 months (&lt;75 y.o) with no significant difference on univariate or multivariate analysis (HR: 1.1 [0.69, 1.74;] p = 0.697. Median OS was 32.4 months for the ≥75 y.o cohort and 32.3 months for the &lt;75 y.o cohort (HR: 1.38 [0.88, 2.17;] p = 0.156). The 5 most common SEs by group are reported below. Of note, adults ≥75 y.o were more likely to report edema compared to the &lt;75 y.o pts (8.2% vs 21.4%, p-value = .026). Conclusions: Pts ≥75 on ART experienced similar survival benefits compared with pts &lt;75. While older adults were more likely to report edema, overall tx toxicity profiles did not differ significantly. Ultimately, these findings ground evidence-based counseling and tx for older adults with mCRPC considering ART. [Table: see text]